Use of insecticides and repellents to control insect vectors is an important strategy for fighting some of the most devastating human diseases, such as malaria. Many insecticides and insect repellents used today target components of the insect nervous system, such as voltage-gated sodium channels and the olfaction system. Two decades ago, a sodium channel-like gene, called DSC1 (Drosophila sodium channel 1), was cloned from Drosophila melanogaster. Although for nearly two decades DSC1 had been thought to encode a voltage-gated sodium channel based on its sequence similarity to sodium channels, we recently showed that DSC1 and its orthologue in cockroach, BSC1, encode the founding members of a novel family of voltage-gated cation channels. Our recent gene knockout experiments suggest that DSC1 plays a crucial role in modulating D. melanogaster sensitivity to DEET (an insect repellent) and deltamethrin (a pyrethroid insecticide), implicating DSC1-family cation channels as important players in insect neurophysiology and toxicology. The long-term goal of this project is to reach a comprehensive understanding of the role of the DSC1 family of cation channels in modulating insect neuronal circuitry and sensitivity to insecticides, attractants, and repellents. An integrated molecular, electrophysiological, pharmacological, and genetic approach will be taken to achieve this goal. Specific aims of the proposed grant period are: 1) molecular and electrophysiological characterization of the DSC1 family of cation channels;2) determination of the role of the DSC1 family of cation channels in insect chemosensation and neurotoxicology;and 3) understanding the role of the DSC1 channel in modulating specific neural circuits. This basic research should enhance our fundamental knowledge of the role of a newly discovered family of ion channels in insect neurophysiology and toxicology. Results could provide a basis for future development of a new generation of insecticides or new methods to enhance the efficacy of currently used insecticides, attractants, or repellents. PUBLIC HEALTH RELEVANCE Development of new strategies for effective control of insect vectors of human diseases, including malaria, is urgently needed. This proposal is aimed at understanding the role of a new family of insect ion channels in neurophysiology and neurotoxicology. This research has the potential to provide a basis for future development of a new generation of insecticides or new methods to enhance the efficacy of currently used insecticides, attractants, or repellents.